3 or 4-substituted piperidine compounds

ABSTRACT

There are disclosed racemic or enantiomerically enriched 3- or 4-substituted piperidine compounds represented by the following structural formula (I): 
     
       
         
         
             
             
         
       
     
     or any of their isomers, or pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions containing the subject compounds. The subject compounds are useful for the treatment of diseases of the central nervous system, particularly depression, anxiety and pain disorder

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/477,369, filed Jun. 3, 2009, which claims priority from U.S.Provisional Application Ser. No. 61/059,289, filed Jun. 6, 2008, thedisclosure of which is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention relates, in general, to racemic orenantiomerically enriched novel 3 or 4-substituted piperidinederivatives and pharmaceutically useful salts thereof, a pharmaceuticalcomposition comprising an effective amount of racemic orenantiomerically enriched novel 3 or 4-substituted piperidinederivatives as monoamine neurotransmitter re-uptake inhibitors to treatcentral nervous system diseases and a method of treating central nervoussystem diseases in a mammal. More particularly, the present inventionrelates to racemic or enantiomerically enriched novel 3-substitutedpiperidine derivatives having various azole moieties andpharmaceutically useful salts thereof, useful to treat the diseases ofthe central nervous system such as depression, anxiety and paindisorder.

BACKGROUND OF THE INVENTION

The three biogenic amines, serotonin, norepinephrine and dopamine aremost closely linked to CNS disorders such as depression. The majority ofantidepressants in current use selectively inhibit the reuptake ofserotonin and/or norepinephrine. Although a strong dopamine re-uptakeinhibiting activity is considered with the risk of undesirable centralstimulation effects, many reports have disclosed that the triplemonoamine neurotransmitter, i.e serotonin, norepinephrine and dopaminere-uptake inhibitors are useful for the treatment of CNS disorders suchas depression, anxiety, attention deficit hyperactivity disorder,obesity, drug addiction and pain disorder. For example, InternationalPatent Application No. WO 2004/072071 discloses the novel8-aza-bicyclo[3,2,1]octane derivatives useful as monoamineneurotransmitter re-uptake inhibitors.

3-Substituted piperidine compounds are effectively used for controllingvarious central nervous system (CNS) disorders. For example,International Patent Application No. WO 02/51837 discloses 3-substitutedpiperidine derivatives that are suitable for treating anxiety,depression, sleep disorder. Active research and development efforts havecontinued to be directed to the application of 3-substituted piperidinecompounds for the treatment of CNS disorders.

SUMMARY OF THE INVENTION

A principal object of the present invention is to provide 3 or4-substituted piperidine derivatives, represented by the followingstructural formula (I):

or any of its isomers or pharmaceutically acceptable salts thereof

wherein

A is selected from the group consisting of phenyl, naphthyl,benzothiophenyl, pyridyl, quinolyl and isoquinolyl which may besubstituted with one or more identical or different substituentsselected from the group consisting of hydrogen, halogen, straight- orbranched-chain C_(1˜4) alkyl, straight- or branched-chain C_(1˜3)alkoxy, nitro, cyano, trifluoromethyl, trifluoromethoxy,methanesulfonyl, phenyloxy, phenyl and thienyl;

B is an azole selected from the group consisting of imidazole, pyrazole,triazole, benzotriazole, tetrazole, 5-methyl tetrazole and 5-phenyltetrazole which are linked by nitrogen as represented by the followingstructural formulae (II):

one of X and Y is carbon and the other is N—R wherein R is hydrogen or aC₁₋₄ alkyl group.

More specifically, the present 3 or 4-substituted piperidine compoundsrepresented by the above formula (I) comprises any of its isomers or anymixture of its isomers represented by the following structural formulae(III) and (IV):

wherein A, B and R are as defined above.

It is another object of the present invention to provide apharmaceutical composition comprising an effective amount of racemic orenantiomerically enriched 3 or 4-substituted piperidine compoundsrepresented by the above structural formula (I), in particular, thecompounds represented by the above structural formulae (III) and (IV)for treating disorders of central nervous system such as depression,anxiety and pain disorder.

It is still another object of the present invention to provide a methodof treating disorders of central nervous system such as depression,anxiety and pain disorder in a mammal in need of such treatment byadministering an effective amount of racemic or enantiomericallyenriched 3 or 4-substituted piperidine compounds represented by theabove structural formula (I), in particular, the compounds representedby the above structural formulae (III), (IV) and a pharmaceuticalacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, the compound represented bythe structural formula (I) and pharmaceutical acceptable salts thereofcan be prepared by techniques and procedures readily available to one ofordinary skill in the art, for example by following the procedures asset forth in the following schemes. These schemes are not intended tolimit the scope of the invention in any way. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

In accordance with the present invention, the compound represented bythe structural formulae (III) and pharmaceutical acceptable saltsthereof can be prepared by the following steps starting from tert-butyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate represented by thefollowing general structural formula (V):

It should be noted that the stereochemistry of piperidine 3-position ofthe general structural formulae (III) depends solely on that of thestarting material (V); a starting material (V) with an (S)-enantiomeryields only a product with (3S)-enantiomer and a starting material (V)with a (R)-enantiomer yields only a product with (3R)-enantiomer.

An example of the method for preparing the general formulae (III) inwhich R is hydrogen, will be described below in detail.

Initially, tort-butyl3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate is reacted withsubstituted phenyl or naphthyl magnesium bromide represented by thefollowing structural formula (VI), (VII) or (VIII):

wherein

R1, R2, R3 is one or more identical or different substituents selectedfrom the group consisting of hydrogen, halogen, straight or branchedchain alkyl of from 1 to 4 carbon atoms, straight or branched chainalkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl; tosynthesize the Boc-protected amino ketone compounds represented by thestructural formula (IX).

wherein

A is selected from the group consisting of phenyl, naphthyl,benzothiophenyl, pyridyl, quinolyl and isoquinolyl which may besubstituted with one or more identical or different substituentsselected from the group consisting of hydrogen, halogen, straight orbranched chain alkyl of from 1 to 4 carbon atoms, straight or branchedchain alkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl.

It is considered that the Boc-protected amino ketone compoundsrepresented by the structural formula (IX) wherein A is benzothiophenyl;pyridyl; quinolyl or isoquinolyl can be prepared through similarmethods.

The compound of formula (IX) is treated with(R)-2-methyl-CBS-oxazaborolidine or (S)-2-methyl-CBS-oxazaborolidinefollowed by Borane-THF complex to synthesize enantiomerically enrichedalcohol compounds represented by the structural formula (X).

The compound of formula (X) is reacted with triphenylphosphine,diisopropyl azodicarboxylate and azole compounds such as imidazole,pyrazole, triazole, tetrazole, 5-methyltetrazole, 5-phenyltetrazole,benzotriazole represented by the structural formula (II) to synthesizethe Boc-protected amino azole compounds represented by the structuralformula (XI)

wherein

A is selected from the group consisting of phenyl, naphthyl,benzothiophenyl, pyridyl, quinolyl and isoquinolyl which may besubstituted with one or more identical or different substituentsselected from the group consisting of hydrogen, halogen, straight orbranched chain alkyl of from 1 to 4 carbon atoms, straight or branchedchain alkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl;

B is selected from the azole group such as imidazole, pyrazole,triazole, benzotriazole, tetrazole, 5-methyl tetrazole and 5-phenyltetrazole which are linked by nitrogen and represented by the followingstructural formula (II):

This intermediate is deprotected by methanolic hydrochloric acidsolution resulting in the 3-substituted piperidine derivativesrepresented by the general formula (XII).

The compound of formula (XII) may be converted into pharmaceuticallyacceptable salts (XIII) by treating with an acid capable of forming apharmacologically useful salt. This procedure is summarized as set forthin Reaction Scheme I below.

Details of the reaction conditions described in Reaction Scheme I are asfollows. For the conversion of the compounds (V) to the compound (IX),it is preferred that the concentration of the starting material (V) isabout 0.005 to 0.1 moles with phenyl or naphthyl magnesium bromideranging from about 2.0 to 3.0 equivalents. This reaction is preferablycarried out at a temperature of 10 to 30° C. The resulting ketonecompound is treated with 0.5 to 1.0 equivalents of (R) or(S)-2-methyl-CBS-oxazaborolidine at a temperature of −78° C. followed byaddition of borane-THF complex ranging from 1.0 to 3.0 equivalents togive the enantiomerically enriched alcohol compound of the formula (X).The resulting alcohol compound is treated with triphenylphosphine,diisopropyl azodicarboxylate and azole compounds raging from 1.0 to 2.5equivalent, preferably carried out at a temperature of about 0 to 30° C.For this reaction, an ethereal solvent such as diethyl ether andtetrahydrofuran or aromatic hydrocarbons such as benzene, toluene andzylene may be used. Compound (XI) is treated with methanolic 6%hydrochloric acid at a temperature of about −10 to 30° C., followed byneutralization to yield the compound of the formula (XII).

In Reaction Scheme I, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom. Specificexamples of the anhydrous acid used for the preparation of the compound(XIII) from the compound (XII) include hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, acetic acid, benzoic acid,carbonic acid, citric acid, malonic acid, salicylic acid, malic acid,fumaric acid, oxalic acid, succinic acid, tartaric acid, lactic acid,gluconic acid, ascorbic acid, maleic acid, aspartic acid,Camphorsulfonic acid, p-toluenesulfonic acid, benzene sulfonic acid,methane sulfonic acid, ethane sulfonic acid, hydroxymethane sulfonicacid and hydroxyethane sulfonic acid and the like. Additional acids canrefer to “Pharmaceutical Salts”, J. Pharm. Sci., 1977; 66(1): 1-19. Thispreparation is executed in a reaction media which can be exemplified byan ethereal solvent such as tetrahydrofuran, an alcoholic solvent suchas methanol, an ester solvent such as ethyl acetate, a halogenatedhydrocarbon solvent, and the mixtures thereof. An ethereal solvent isrecommended as an addition solution, including ethyl ether, propylether, isopropyl ether, butyl ether, isobutyl ether. The concentrationof the compound (XII) is on the order of about 0.01 to 5 moles.

The method for preparing the general formulae (III) in which R is nothydrogen will be described below in detail.

Initially, the prepared amine compounds (XII) is reacted withtriethylamine and an appropriate alkylhalide in dichloromethane at 0° C.to yield the alkylated amine compound represented by the generalformulae (III) in which R is not hydrogen.

The compound of formulae (III) in which R is not hydrogen, may beconverted into pharmaceutically acceptable salts (XIV) as describedabove.

This procedure is summarized as set forth in Reaction Scheme II below.

Details of the reaction conditions described in Reaction Scheme II areas follows. For the conversion of the compounds (XII) to the compound(III), the concentration of the starting material (XII) is about 0.005to 0.1 moles with triethylamine ranging from about 2.0 to 3.0equivalents and alkylhalide ranging from about 1.5 to 3 equivalents.This reaction is preferably carried out at a temperature of 0 to 30° C.For this alkylation, an ethereal solvent such as diethyl ether andtetrahydrofuran, a halogenated hydrocarbon solvent such asdichloromethane and chloroform, an alcohol solvent such as methanol,ethanol and propanol, or the mixture thereof may be used.

In Reaction Scheme II, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom as describedabove.

In accordance with the present invention, the compound represented bythe structural formula (IV) and pharmaceutical acceptable salts thereofcan be prepared by the following steps starting from tert-butyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate represented by thefollowing general structural formula (XV):

An example of the method for preparing the general formula (IV) in whichR is hydrogen, will be described below in detail.

Initially, tert-butyl4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate is reacted withsubstituted phenyl or naphthyl magnesium bromide represented by thefollowing structural formula (VI), (VII) or (VIII):

wherein

R1, R2 or R3 is one or more identical or different substituents selectedfrom the group consisting of hydrogen, halogen, straight- orbranched-chain alkyl of from 1 to 4 carbon atoms, straight or branchedchain alkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl; tosynthesize the Boc-protected amino ketone compounds represented by thestructural formula (XVI).

wherein

A is selected from the group consisting of phenyl, naphthylbenzothiophenyl, pyridyl, quinolyl and isoquinolyl which may besubstituted with one or more identical or different substituentsselected from the group consisting of hydrogen, halogen, straight orbranched chain alkyl of from 1 to 4 carbon atoms, straight or branchedchain alkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl;

It is considered that the Boc-protected amino ketone compoundsrepresented by the structural formula (IX) wherein A is benzothiophenyl,pyridyl, quinolyl or isoquinolyl can be prepared through similar method.

The compound of formula (XVI) is treated with(R)-2-methyl-CBS-oxazaborolidine or (S)-2-methyl-CBS-oxazaborolidinefollowed by Borane-THF complex to synthesize enantiomerically enrichedalcohol compounds represented by the structural formula (XVII).

The compound of formula (XVII) is reacted with triphenylphosphine,diisopropyl azodicarboxylate and azole compounds such as imidazole,pyrazole, triazole, tetrazole, 5-methyltetrazole, 5-phenyltetrazole,benzotriazole represented by the structural formula (II) to synthesizethe Boc-protected amino azole compounds represented by the structuralformula (XVIII)

wherein

A is selected from the group consisting of phenyl, naphthyl,benzothiophenyl, pyridyl, quinolyl and isoquinolyl which may besubstituted with one or more identical or different substituentsselected from the group consisting of hydrogen, halogen, straight orbranched chain alkyl of from 1 to 4 carbon atoms, straight or branchedchain alkoxy of from 1 to 3 carbon atoms, nitro, cyano, trifluoromethyl,trifluoromethoxy, methanesulfonyl, phenyloxy, phenyl and thienyl;

B is selected from the azole group such as imidazole, pyrzole, triazole,benzotriazole, tetrazole, 5-methyl tetrazole or 5-phenyl tetrazole whichare linked by nitrogen and represented by the following structuralformulae (II):

This intermediate is deprotected by methanolic hydrochloric acidsolution resulting in the 4-substituted piperidine derivativesrepresented by the general formula (XIX).

The enantiomeric mixture (XIX) is dissolved in a small amount ofisopropylalcohol and separated by chiral preparative LiquidChromatography. Separation is performed by using a CHIRALPACK OD-Hcolumn (manufactured by Daicel Chemical Industries, Ltd.) as the Prep-LCcolumn, at a column temperature of 25° C., withn-hexane/isopropylalcohol including 0.1% triethylamine (90:10) as theeluent to get pure enantiomers.

The enantiomeric pure compound of formula (XIX) may be converted intopharmaceutically acceptable salts (XX) as described above.

This procedure is summarized as set forth in Reaction Scheme III below.

Details of the reaction conditions described in Reaction Scheme III areas follows. For the conversion of the compounds (XV) to the compound(XVI), it is preferred that the concentration of the starting material(XV) is about 0.005 to 0.1 moles with phenyl or naphthyl magnesiumbromide ranging from about 2.0 to 3.0 equivalents. This reaction ispreferably carried out at a temperature of 10 to 30° C. The resultingketone compound is treated with 0.5 to 1.0 equivalents of (R) or(S)-2-methyl-CBS-oxazaborolidine at a temperature of −78° C. followed byaddition of borane-THF complex ranging from 1.0 to 3.0 equivalents togive the enantiomerically enriched alcohol compound of the formula(XVII). The resulting alcohol compound is treated withtriphenylphosphine, diisopropyl azodicarboxylate and azole compoundsraging from 1.0 to 2.5 equivalents, preferably carried out at atemperature of about 0 to 30° C. For this reaction, an ethereal solventsuch as diethyl ether and tetrahydrofuran or aromatic hydrocarbons suchas benzene, toluene and zylene may be used. Compound (XVIII) is treatedwith methanolic 6% hydrochloric acid at a temperature of about −10 to30° C., followed by neutralization to yield the compound of the formula(XIX).

In Reaction Scheme III, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom as describedabove.

The method for preparing the general formula (IV) in which R is nothydrogen, will be described below in detail.

Initially, the prepared amine compounds (XIX) is reacted withtriethylamine and an appropriate alkylhalide in dichloromethane at 0° C.to yield the alkylated amine compound represented by the general formula(IV) in which R is not hydrogen.

The compound of formula (IV) in which R is not hydrogen, may beconverted into pharmaceutically acceptable salts (XXI) as describedabove.

This procedure is summarized as set forth in Reaction Scheme IV below.

Details of the reaction conditions described in Reaction Scheme IV areas follows. For the conversion of the compounds (XIX) to the compound(IV), the concentration of the starting material (XIX) is about 0.005 to0.1 moles with triethylamine ranging from about 2.0 to 3.0 equivalentsand alkylhalide ranging from about 1.5 to 3 equivalents. This reactionis preferably carried out at a temperature of 0 to 30° C. For thisalkylation, an ethereal solvent such as diethyl ether andtetrahydrofuran, a halogenated hydrocarbon solvent such asdichloromethane and chloroform, an alcohol solvent such as methanol,ethanol and propanol, or the mixture thereof may be used.

In Reaction Scheme IV, HX represents an acid capable of forming apharmacologically useful salt with the basic nitrogen atom as describedabove.

Representative examples of the compounds (I), (III) and (IV) from schemeI, II, III and IV include the following compounds:

-   (3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine-   (3R)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine-   (3S)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine-   (3R)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine-   (3R)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine-   (3R)-3-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(S)-phenyl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-phenyl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-{(S)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine-   (3S)-3-{(R)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine-   (3S)-3-[(S)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(S)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine-   (3S)-3-[(S)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-{(S)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine-   (3S)-3-{(R)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine-   (3S)-3-[(S)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-1-ethyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-naphthalen-2-yl(5-phenyl-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-2-yl(5-phenyl-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-naphthalen-2-yl(5-phenyl-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(5-phenyl-tetrazol-2-yl)methyl]piperidine-   1-{(S)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole-   1-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole-   2-{(5)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole-   2-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole-   (3S)-3-[(R)-1-benzothiophene-3-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(4H-1,2,4-triazol-4-yl)methyl]piperidine-   (3S)-3-[(S)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperidine-   (3S)-3-[(R)-naphthalen-2-yl(1H-pyrazol-1-yl)methyl]piperidine-   (3S)-3-[(S)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine-   (3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine-   (3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine-   (3S)-1-butyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   4-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   4-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine-   4-[(S)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine-   4-[(R)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine-   4-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   4-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine-   4-[(S)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine-   4-[(R)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine-   4-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine-   4-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine-   4-[(S)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine-   4-[(R)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine-   4-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine-   4-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

A better understanding of the present invention may be obtained in lightof following examples which are set forth to illustrate, but are not tobe construed to limit, the present invention.

Example 1 (3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

A mixture of 2-bromonaphthalene (4.59 mmol) and magnesium (5.508 mmol)was stirred vigorously in anhydrous THF (10 ml) under nitrogenatmosphere for 1 h to prepare naphthalen-2-ylmagnesium bromide solution.To this resulting solution was added tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.836 mmol)slowly at 0° C. After 10 min, the reaction mixture was warmed up to roomtemperature slowly and stirred for 2 hours. This solution was thenquenched with aqueous NH₄Cl (10 ml) and ethyl acetate (15 ml) was added.Organic layer was separated from aqueous layer, washed with brine. Thecombined organic layer was dried over anhydrous MgSO₄ and concentratedin vacuo.

The crude product was dissolved in anhydrous THF. To this solution wasslowly added (S)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 0.5equiv) at −78° C. After 5 min, borane-THF complex (3 equiv) was addedslowly. The reaction mixture was then transferred into the freezer andleft overnight. Chiral LC showed 9:1 ratio of the S to R isomer. Themixture was cooled to 0° C. and water was added dropwise to quench thereaction. The reaction mixture was diluted with ethyl acetate, washedwith 5% aq NaOH, water, brine, and dried over MgSO₄. Afterconcentration, the crude product was purified by flash columnchromatography with a 4-35% ethyl acetate in hexanes gradient to afford(R)-tert-butyl 3-((S)-hydroxy(naphthyl)methyl)piperidine-1-carboxylate.

To a stirred solution of triphenylphosphine (2.754 mmol) and1H-tetrazole (2.754 mmol) in THF (6 ml) was added previously preparedproduct (1.836 mmol) in THF (2 ml) at room temperature. The reactionmixture was stirred for 15 minutes, followed by the dropwise addition ofdiisopropyl azodicarboxylate (3.672 mmol) at 0° C. The solution wasfurther stirred for 1 hour at room temperature. When the reaction wascomplete, the crude mixture was purified with silica gel chromatography(ethyl acetate:hexane=1 : 6).

The resulting product was dissolved in 6% HCl-MeOH solution and allowedto stir for 6 h. The solvent was removed under reduced pressure andbasified with 1N NaOH to afford(3R)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (m,2H), 6.0 (d, 1H), 3.0 (br, 2H), 2.5 (br, 3H), 1.5 (br, 3H), 1.2 (m, 2H)

Example 2 (3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using tert-butyl(3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate as a reactant,instead of tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. As a reducingagent, (R)-2-methyl-CBS-oxazaborolidine was used instead of(S)-2-methyl-CBS-oxazaborolidine, to give(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.7 (m,1H), 7.5 (m, 2H), 6.0 (d, 1H), 3.0 (br, 2H), 2.5 (br, 3H), 1.5 (br, 3H),1.2 (m, 2H)

Example 3 (3R)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using(R)-2-methyl-CBS-oxazaborolidine as a reducing agent, instead of(S)-2-methyl-CBS-oxazaborolidine, to give(3R)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidinehydrochloride.

1H-NMR (DMSO, 200 MHz), δ9.1 (br, 1H), 8.2 (s, 1H), 8.0 (m, 3H), 7.7 (d,1H), 7.6 (m, 2H), 6.2 (d, 1H), 2.8 (br, 2H), 2.5 (br, 3H), 1.6 (br, 2H),1.3 (br, 3H)

Example 4 (3S)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using tert-butyl(3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate as a reactant,instead of tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate, to give(3S)-3-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidinehydrochloride.

1H-NMR (DMSO, 200 MHz), δ9.1 (br, 1H), 8.2 (s, 1H), 8.0 (m, 3H), 7.7 (d,1H), 7.6 (m, 2H), 6.2 (d, 1H), 2.8 (br, 2H), 2.5 (br, 3H), 1.6 (br, 2H),1.3 (br, 3H)

Example 5 (3R)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 1 to give(3R)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ9.0 (s, 1H), 7.8 (m, 4H), 7.5 (m, 3H), 5.8 (d,1H), 4.8 (br, 1H), 3.0 (br, 4H), 2.5 (br, 1H), 1.6 (br, 3H)

Example 6 (3S)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 2 to give(3S)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ9.0 (s, 1H), 7.8 (m, 4H), 7.5 (m, 3H), 5.8 (d,1H), 4.8 (br, 1H), 3.0 (br, 4H), 2.5 (br, 1H), 1.6 (br, 3H)

Example 7 (3R)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 3 to give(3R)-3-[(S)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidinehydrochloride.

1H-NMR (DMSO, 200 MHz), δ9.8 (s, 1H), 8.0 (m, 4H), 7.6 (m, 3H), 6.0 (d,1H), 2.8 (br, 2H), 2.5 (br, 2H), 2.3 (m, 1H), 1.6 (br, 2H), 1.3 (br, 3H)

Example 8 (3S)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 4 to give(3S)-3-[(R)-naphthalen-2-yl(1H-tetrazol-1-yl)methyl]piperidinehydrochloride.

1H-NMR (DMSO, 200 MHz), δ9.8 (s, 1H), 8.0 (m, 4H), 7.6 (m, 3H), 6.0 (d,1H), 2.8 (br, 2H), 2.5 (br, 2H), 2.3 (m, 1H), 1.6 (br, 2H), 1.3 (br, 3H)

Example 9(3S)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole. Also, as areactant, tert-butyl(3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was usedinstead of tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate to give(3S)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.0 (m, 1H), 7.8 (br, 3H), 7.7 (m, 1H), 7.5(m, 2H), 5.8 (d, 1H), 2.9 (br, 2H), 2.8 (br, 2H), 2.5 (d, 3H), 2.4 (m,1H), 1.7 (br, 1H), 1.5 (br, 2H), 1.2 (br, 2H)

Example 10(3S)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using tert-butyl(3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was usedinstead of tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. As a reducingagent, (R)-2-methyl-CBS-oxazaborolidine was used instead of(S)-2-methyl-CBS-oxazaborolidine. And 5-methyl-1H-tetrazole was used asa reactant, instead of 1H-tetrazole, to give(3S)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ7.9 (br, 4H), 7.7 (m, 1H), 7.5 (m, 2H), 5.8(d, 1H)

Example 11(3R)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole. Also, as areducing agent, (R)-2-methyl-CBS-oxazaborolidine was used instead of(S)-2-methyl-CBS-oxazaborolidine, to give(3R)-3-[(S)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.0 (s, 1H), 7.8 (br, 3H), 7.7 (d, 1H), 7.5(m, 2H), 5.8 (d, 1H), 2.9 (br, 2H), 2.6 (br, 2H), 2.5 (d, 3H), 2.4 (m,1H), 1.5 (m, 3H), 1.2 (m, 2H)

Example 12(3R)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-(5-methyl-2H-tetrazol-2-yl)(naphthalen-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ7.9 (m, 5H), 7.7 (d, 1H), 7.5 (m, 2H), 5.8 (d,1H), 3.0 (m, 3H), 2.6 (m, 1H), 2.5 (s, 3H), 2.4 (m, 1H), 1.5 (br, 5H)

Example 13(3R)-3-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using 1H-[1,2,3]-triazoleas a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.0 (s, 1H), 7.8 (d, 3H), 7.7 (d, 1H), 7.6 (s,1H), 7.5 (m, 2H), 5.6 (d, 1H), 3.0 (m, 2H), 2.5 (m, 3H), 1.5 (br, 3H),1.2 (m, 2H)

Example 14(3S)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using tert-butyl(3S)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate was usedinstead of tert-butyl(3R)-3-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate. As a reducingagent, (R)-2-methyl-CBS-oxazaborolidine was used instead of(S)-2-methyl-CBS-oxazaborolidine. And 1H-[1,2,3]-triazole was used as areactant, instead of 1H-tetrazole, to give(3S)-3-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.0 (s, 1H), 7.8 (d, 3H), 7.7 (d, 1H), 7.6 (s,1H), 7.5 (m, 2H), 5.6 (d, 1H), 3.0 (m, 2H), 2.5 (m, 3H), 1.5 (br, 3H),1.2 (m, 2H)

Example 15(3R)-3-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using4-bromo-1,2-dichlorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (s, 1H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.6 (br, 3H), 2.3 (br, 1H), 1.6 (br, 3H), 1.2 (m, 2H)

Example 16(3S)-3-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using4-bromo-1,2-dichlorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (s, 1H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.6 (br, 3H), 2.3 (br, 1H), 1.6 (br, 3H), 1.2 (m, 2H)

Example 17(3R)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using1-bromo-4-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3R)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.7 (br, 1H), 2.4 (br, 1H), 1.7 (br,1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 18(3S)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.7 (br, 1H), 2.4 (br, 1H), 1.7 (br,1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 19(3R)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using1-bromo-4-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3R)-3-[(S)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.7 (br, 1H), 2.4 (br, 1H), 1.7 (br,1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 20(3S)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 2H), 5.8 (d,1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.7 (br, 1H), 2.4 (br, 1H), 1.7 (br,1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 21(3R)-3-[(R)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using 1-bromonaphthaleneas a reactant, instead of 2-bromonaphthalene, to give(3R)-3-[(R)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (m,2H), 7.6 (m, 3H), 6.8 (d, 1H), 3.2 (br, 3H), 2.6 (br, 2H), 1.6 (br, 3H),1.2 (br, 2H)

Example 22(3S)-3-[(S)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using 1-bromonaphthaleneas a reactant, instead of 2-bromonaphthalene, to give(3S)-3-[(S)-naphthalen-1-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (m,2H), 7.6 (m, 3H), 6.8 (d, 1H), 3.2 (br, 3H), 2.6 (br, 2H), 1.6 (br, 3H),1.2 (br, 2H)

Example 23(3R)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using1-bromo-4-isopropylbenzene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 3.2 (br, 1H), 3.0 (br, 1H), 2.9 (m, 2H), 2.6 (br, 2H), 1.7 (br,3H), 1.2 (d, 6H), 1.1 (m, 1H)

Example 24(3S)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-isopropylbenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 3.2 (br, 1H), 3.0 (br, 1H), 2.9 (m, 2H), 2.6 (br, 2H), 1.7 (br,3H), 1.2 (d, 6H), 1.1 (m, 1H)

Example 25(3R)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using1-bromo-4-isopropylbenzene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(S)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 4.0 (br, 1H), 3.0 (br, 1H), 2.8 (m, 3H), 2.6 (br, 1H), 2.4 (br,1H), 1.7 (br, 1H), 1.5 (br, 1H), 1.3 (m, 2H), 1.2 (d, 6H), 1.1 (m, 1H)

Example 26(3S)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-isopropylbenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(4-isopropylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 4.0 (br, 1H), 3.0 (br, 1H), 2.8 (m, 3H), 2.6 (br, 1H), 2.4 (br,1H), 1.7 (br, 1H), 1.5 (br, 1H), 1.3 (m, 2H), 1.2 (d, 6H), 1.1 (m, 1H)

Example 27(3S)-3-[(S)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using4-bromo-1,2-dimethoxybenzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-[(S)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.1 (d, 2H), 6.8 (d, 1H), 5.8 (d,1H), 3.9 (d, 6H), 2.5 (br, 5H), 1.6 (br, 3H), 1.2 (br, 2H)

Example 28(3S)-3-[(R)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using4-bromo-1,2-dimethoxybenzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-[(R)-(3,4-dimethoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.1 (m, 2H), 6.8 (d, 1H), 5.7 (d,1H), 3.9 (d, 1H), 2.8 (m, 4H), 2.4 (m, 1H), 1.5 (br, 3H), 1.2 (br, 2H)

Example 29(3S)-3-[(S)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 27 to give(3S)-3-[(S)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.7 (s, 1H), 7.0 (br, 2H), 6.9 (d, 1H), 5.6(d, 1H), 3.9 (d, 6H), 2.8 (br, 4H), 2.4 (br, 1H), 1.6 (br, 4H), 1.2 (br,1H)

Example 30(3S)-3-[(R)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 28 to give(3S)-3-[(R)-(3,4-dimethoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.6 (s, 1H), 7.0 (d, 2H), 6.8 (d, 2H), 5.4 (d,1H), 3.9 (d, 6H), 2.8 (m, 4H), 2.4 (m, 1H), 1.6 (br, 4H), 1.1 (m, 1H)

Example 31 (3S)-3-[(S)-phenyl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using bromobenzene as areactant, instead of 2-bromonaphthalene to give(3S)-3-[(S)-phenyl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 3H), 5.8 (d,1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.6 (m, 2H), 2.4 (m, 1H), 1.6 (br, 3H),1.2 (m, 2H)

Example 32 (3S)-3-[(R)-phenyl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using bromobenzene as areactant, instead of 2-bromonaphthalene to give(3S)-3-[(R)-phenyl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.4 (m, 3H), 5.8 (d,1H), 3.0 (m, 1H), 2.8 (d, 2H), 2.6 (m, 1H), 2.4 (m, 1H), 1.7 (br, 1H),1.5 (br, 1H), 1.3 (br, 2H), 1.2 (m, 1H)

Example 33 (3S)-3-(S)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methylpiperidine

The procedure given in Example 2 was followed using1-bromo-4-(trifluoromethyl)benzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-{(S)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.6 (s, 1H), 7.7 (m, 4H), 5.9 (d, 1H), 3.0(br, 1H), 2.8 (br, 1H), 2.6 (br, 2H), 2.4 (br, 1H), 1.5 (br, 3H), 1.2(br, 2H)

Example 34(3S)-3-{(R)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine

The procedure given in Example 4 was followed using1-bromo-4-(trifluoromethyl)benzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-{(R)-2H-tetrazol-2-yl[4-(trifluoromethyl)phenyl]methyl}piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.7 (m, 4H), 5.9 (d, 1H), 3.0(br, 1H), 2.8 (br, 3H), 2.4 (br, 1H), 1.7 (br, 2H), 1.4 (br, 2H), 1.2(br, 1H)

Example 35(3S)-3-[(S)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using2-bromo-6-methoxynaphthalene as a reactant, instead of2-bromonaphthalene to give(3S)-3-[(S)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.9 (br, 1H), 7.7 (m, 3H), 7.2(m, 2H), 5.9 (d, 1H), 3.9 (s, 1H), 3.0 (br, 2H), 2.6 (br, 3H), 1.6 (br,3H), 1.2 (br, 2H)

Example 36(3S)-3-[(R)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-6-methoxynaphthalene as a reactant, instead of2-bromonaphthalene to give(3S)-3-[(R)-(6-methoxynaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.9 (s, 1H), 7.7 (m, 3H), 7.2 (m,2H), 5.9 (d, 1H), 3.9 (s, 1H), 3.0 (br, 2H), 2.5 (br, 3H), 1.4 (br, 5H)

Example 37(3S)-3-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-methylbenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 3H), 2.3 (s, 3H), 1.6 (br,3H), 1.2 (br, 2H)

Example 38(3S)-3-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-methylbenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.4 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 3.0 (br, 1H), 2.7 (br, 4H), 2.3 (s, 3H), 1.6 (br, 2H), 1.4 (br,1H), 1.2 (br, 2H)

Example 39(3S)-3-[(S)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-3-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (s, 1H), 7.4 (m, 1H), 7.3 (m,2H), 5.8 (d, 1H), 3.0 (br, 1H), 2.7 (m, 3H), 2.4 (m, 1H), 2.2 (br, 1H),1.6 (br, 3H), 1.2 (m, 1H)

Example 40(3S)-3-[(R)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-3-chlorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(3-chlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (s, 1H), 7.4 (m, 1H), 7.3 (m,2H), 5.8 (d, 1H), 3.0 (m, 1H), 2.7 (m, 3H), 2.4 (m, 1H), 1.7 (br, 2H),1.4 (m, 2H), 1.2 (m, 1H)

Example 41(3S)-3-[(S)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-2,4-difluorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.7 (m, 1H), 6.9 (m, 2H), 6.2 (d,1H), 3.0 (br, 1H), 2.5 (br, 4H), 1.7 (br, 3H), 1.4 (br, 1H), 1.2 (br,1H)

Example 42(3S)-3-[(R)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-2,4-difluorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(2,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.8 (m, 1H), 6.9 (m, 2H), 6.2 (d,1H), 3.0 (m, 1H), 2.7 (m, 3H), 2.4 (m, 1H), 2.0 (br, 1H), 1.7 (br, 1H),1.5 (br, 1H), 1.2 (m, 2H)

Example 43(3S)-3-[(S)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-methoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.5 (d, 2H), 6.9 (d, 2H), 5.7 (d,1H), 3.8 (s, 3H), 3.0 (br, 1H), 2.6 (br, 4H), 1.6 (br, 4H), 1.2 (br, 1H)

Example 44(3S)-3-[(R)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-methoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.5 (d, 2H), 6.9 (d, 2H), 5.7 (d,1H), 3.8 (s, 3H), 2.8 (br, 4H), 2.3 (br, 1H), 1.8 (br, 2H), 1.3 (br, 3H)

Example 45(3S)-3-[(S)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 43 to give(3S)-3-[(S)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.6 (s, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 5.5 (d,1H), 3.8 (s, 3H), 2.9 (br, 1H), 2.7 (br, 3H), 2.3 (br, 1H), 1.6 (br,4H), 1.2 (br, 1H)

Example 46(3S)-3-[(R)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 44 to give(3S)-3-[(R)-(4-methoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.6 (s, 1H), 7.4 (d, 2H), 6.9 (d, 2H), 5.4 (d,1H), 3.8 (s, 3H), 2.8 (br, 4H), 2.4 (br, 1H), 1.8 (br, 2H), 1.5 (br,2H), 1.1 (br, 1H)

Example 47(3S)-3-[(S)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-phenoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.6 (s, 1H), 7.5 (d, 2H), 7.4 (m, 3H), 7.2 (m,1H), 7.0 (m, 5H), 5.8 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 1H),2.5 (br, 1H), 2.4 (br, 1H), 1.6 (br, 3H), 1.5 (br, 1H), 1.2 (m, 1H)

Example 48(3S)-3-[(R)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-phenoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-phenoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.6 (d, 2H), 7.4 (m, 3H), 7.1 (m,1H), 7.0 (m, 5H), 5.8 (d, 1H), 3.0 (br, 1H), 2.9 (d, 1H), 2.8 (d, 1H),2.7 (br, 1H), 2.4 (br, 1H), 1.7 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H),1.1 (m, 1H)

Example 49(3S)-3-[(S)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 47 to give(3S)-3-[(S)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.7 (s, 1H), 7.4 (m, 5H), 7.2 (m, 1H), 7.0 (m,5H), 5.6 (d, 1H), 2.9 (br, 1H), 2.8 (br, 3H), 2.4 (br, 1H), 1.7 (br,2H), 1.5 (br, 2H), 1.2 (br, 1H)

Example 50(3S)-3-[(R)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine

The procedure was given in Example 48 to give(3S)-3-[(R)-(4-phenoxyphenyl)(1H-tetrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.6 (s, 1H), 7.4 (m, 5H), 7.2 (m, 1H), 7.0 (m,5H), 5.4 (d, 1H), 3.0 (br, 1H), 2.9 (br, 1H), 2.7 (br, 2H), 2.4 (br,1H), 1.7 (br, 2H), 1.5 (br, 2H), 1.2 (br, 1H)

Example 51(3S)-3-[(S)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-fluorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.0 (t, 2H), 5.8 (d,1H), 2.9 (br, 1H), 2.5 (br, 4H), 1.6 (br, 4H), 1.2 (br, 1H)

Example 52(3S)-3-[(R)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-fluorobenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-fluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.6 (m, 2H), 7.0 (t, 2H), 5.8 (d,1H), 2.9 (br, 1H), 2.7 (br, 3H), 2.4 (br, 1H), 1.7 (br, 2H), 1.3 (br,3H)

Example 53 (3S)-3-[(S)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using 4-bromobiphenyl as areactant, instead of 2-bromonaphthalene to give(3S)-3-[(S)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.5 (m, 11H), 5.9 (d, 1H), 3.0(br, 4H), 2.6 (br, 2H), 1.7 (br, 2H), 1.3 (br, 2H)

Example 54 (3S)-3-[(R)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using 4-bromobiphenyl as areactant, instead of 2-bromonaphthalene to give(3S)-3-[(R)-biphenyl-4-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 7.5 (m, 11H), 5.8 (d, 1H), 3.0(br, 4H), 2.6 (br, 2H), 1.7 (br, 2H), 1.2 (br, 2H)

Example 55(3S)-3-{(S)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine

The procedure given in Example 2 was followed using1-bromo-3-(trifluoromethyl)benzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-{(S)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.8 (d, 2H), 7.6 (m, 2H), 5.9 (d,1H), 3.0 (br, 1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.4 (m, 1H),1.8 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.5 (1H), 1.2 (m, 1H)

Example 56(3S)-3-{(R)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine

The procedure given in Example 4 was followed using1-bromo-3-(trifluoromethyl)benzene as a reactant, instead of2-bromonaphthalene to give(3S)-3-{(R)-2H-tetrazol-2-yl[3-(trifluoromethyl)phenyl]methyl}piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.5 (m,1H), 5.9 (d, 1H), 3.0 (br, 1H), 2.8 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H),1.7 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H), 1.1 (br, 1H)

Example 57(3S)-3-[(S)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-propylbenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (br, 2H), 7.2 (br, 2H), 5.8(d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 4H), 2.4 (br, 1H), 1.6(br, 5H), 1.5 (br, 1H), 1.1 (br, 1H), 1.0 (t, 3H)

Example 58(3S)-3-[(R)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-propylbenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(4-propylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (d, 2H), 7.2 (d, 2H), 5.7 (d,1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.6 (br, 3H), 2.4 (br, 1H), 1.7 (br,3H), 1.5 (br, 1H), 1.3 (br, 1H), 1.1 (br, 1H), 1.0 (t, 3H)

Example 59(3S)-3-[(S)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-methylnaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 7.9 (d,1H), 7.6 (m, 2H), 7.4 (d, 1H), 6.8 (d, 1H), 3.1 (br, 2H), 2.7 (s, 3H),2.6 (br, 3H), 2.5 (br, 1H), 1.7 (br, 2H), 1.5 (br, 1H), 1.2 (m, 1H)

Example 60(3S)-3-[(R)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-methylnaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(4-methylnaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 8.0 (d,1H), 7.6 (m, 2H), 7.4 (d, 1H), 6.8 (d, 1H), 3.1 (br, 2H), 2.9 (br, 1H),2.7 (s, 3H), 2.6 (br, 1H), 2.4 (br, 1H), 2.2 (br, 1H), 1.8 (br, 1H), 1.6(br, 1H), 1.3 (m, 2H)

Example 61(3S)-3-[(S)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-3-methylbenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.4 (s, 2H), 7.3 (t, 1H), 7.1 (d,1H), 5.7 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 1H), 2.4 (br,1H), 2.3 (s, 3H), 1.7 (br, 1H), 1.6 (br, 1H), 1.4 (br, 1H), 1.1 (m, 1H)

Example 62(3S)-3-[(R)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-brorno-3-methylbenzene as a reactant, instead of 2-bromonaphthalene togive ((3S)-3-[(R)-(3-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.4 (m, 2H), 7.3 (t, 1H), 7.1 (d,1H), 5.7 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 1H), 2.4 (br,1H), 2.3 (s, 3H), 1.7 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H), 1.1 (m, 1H)

Example 63(3S)-3-[(S)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-3-methoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(S)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.3 (t, 1H), 7.1 (d, 2H), 6.9 (d,1H), 5.7 (d, 1H), 3.8 (s, 3H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 2H),2.4 (br, 1H), 1.6 (br, 3H), 1.4 (br, 1H), 1.1 (m, 1H)

Example 64(3S)-3-[(R)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-3-methoxybenzene as a reactant, instead of 2-bromonaphthalene togive (3S)-3-[(R)-(3-methoxyphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.3 (t, 1H), 7.1 (d, 2H), 6.9 (d,1H), 5.7 (d, 1H), 3.8 (s, 3H), 3.0 (br, 1H), 2.8 (br, 2H), 2.6 (br, 1H),2.4 (br, 1H), 1.7 (br, 2H), 1.4 (br, 1H), 1.3 (br, 1H), 1.1 (m, 1H)

Example 65(3S)-3-[(S)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using5-bromo-1-benzothiophene as a reactant, instead of 2-bromonaphthalene togive(3S)-3-[(S)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.5(dd, 2H), 7.3 (d, 1H), 5.9 (d, 1H), 2.9 (br, 2H), 2.6 (br, 2H), 2.4 (br,2H), 1.6 (br, 2H), 1.4 (br, 1H), 1.2 (br, 1H)

Example 66(3S)-3-[(R)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using5-bromo-1-benzothiophene as a reactant, instead of 2-bromonaphthalene togive(3S)-3-[(R)-1-benzothiophene-5-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.9 (d, 1H), 7.5(dd, 2H), 7.3 (d, 1H), 5.9 (d, 1H), 2.9 (br, 3H), 2.6 (br, 1H), 2.4 (br,1H), 2.0 (br, 1H), 1.7 (br, 1H), 1.4 (br, 2H), 1.2 (br, 1H)

Example 67(3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using2-bromo-6-chloronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (d,1H), 6.0 (d, 1H), 3.0 (dd, 2H), 2.6 (m, 2H), 2.4 (t, 1H), 1.8 (br, 1H),1.7 (br, 1H), 1.6 (br, 1H), 1.4 (m, 1H), 1.2 (m, 1H)

Example 68(3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using2-bromo-6-chloronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (d,1H), 6.0 (d, 1H), 3.0 (dd, 2H), 2.6 (m, 2H), 2.4 (t, 1H), 1.8 (br, 1H),1.7 (br, 1H), 1.6 (br, 1H), 1.4 (m, 1H), 1.2 (m, 1H)

Example 69(3R)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using2-bromo-6-chloronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(S)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (d,1H), 6.0 (d, 1H), 3.0 (dd, 2H), 2.8 (d, 1H), 2.7 (t, 1H), 2.4 (t, 1H),1.7 (br, 2H), 1.5 (m, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 70(3S)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-6-chloronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(6-chloronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (d,1H), 6.0 (d, 1H), 3.0 (dd, 2H), 2.8 (d, 1H), 2.7 (t, 1H), 2.4 (t, 1H),1.7 (br, 2H), 1.5 (m, 1H), 1.4 (br, 1H), 1.2 (m, 1H)

Example 71(3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yflmethyl]piperidine

The procedure given in Example 2 was followed using2-bromo-6-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.4 (m,2H), 6.0 (d, 1H), 3.0 (br, 2H), 2.7 (br, 2H), 2.5 (m, 1H), 1.6 (br, 3H),1.2 (m, 2H)

Example 72(3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-6-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.4 (m,2H), 6.0 (d, 1H), 3.0 (br, 2H), 2.6 (br, 2H), 2.2 (br, 1H), 1.8 (br,1H), 1.4 (br, 2H), 1.2 (br, 2H)

Example 73(3S)-1-ethyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

(3S)-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine (2.0mmol) from Example 2 was dissolved in acetonitrile and the solution wastreated with triethylamine (3.0 mmol) at room temperature. To thissolution was added iodoethane in acetonitrile slowly and the solutionwas warmed up to 40° C. After the completion of the reaction, thereaction mixture was diluted with ethyl acetate, washed with 5% aq NaOH,water, brine, and dried over MgSO₄. After concentration, the crudeproduct was purified by flash column chromatography with a 10% Methanolin dichloromethane to afford(3S)-1-ethyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ8.6 (s, 1H), 8.0 (d, 1H), 7.9 (m, 3H), 7.7 (d,1H), 7.5 (m, 2H), 6.1 (d, 1H), 3.2 (br, 1H), 2.8 (br, 1H), 2.4 (m, 3H),2.2 (br, 1H), 2.0 (m, 1H), 1.7 (br, 3H), 1.4 (br, 1H), 1.0 (m, 4H)

Example 74(3R)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (d, 2H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (m,5H), 6.0 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.6 (br, 2H), 1.6 (br,3H), 1.3 (br, 2H)

Example 75(3S)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (d, 2H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (m,5H), 6.0 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.6 (br, 2H), 1.6 (br,3H), 1.3 (br, 2H)

Example 76(3R)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(S)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (d, 2H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (m,5H), 5.9 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.6 (br, 2H), 1.8 (br,1H), 1.7 (br, 2H), 1.2 (br, 2H)

Example 77(3S)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(R)-naphthalen-2-yl-(5-phenyl-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (d, 2H), 8.0 (s, 1H), 7.8 (m, 4H), 7.5 (m,5H), 5.9 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.6 (br, 2H), 1.8 (br,1H), 1.7 (br, 2H), 1.2 (br, 2H)

Example 781-{(S)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole

The procedure given in Example 2 was followed using benzotriazole as areactant, instead of 1H-tetrazole to give1-{(5)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole.

1H-NMR (CDCl₃, 500 MHz), δ8.0 (d, 1H), 7.9 (s, 1H), 7.8 (m, 3H), 7.6 (m,2H), 7.5 (m, 2H), 7.4 (t, 1H), 7.3 (t, 1H), 5.9 (d, 1H), 3.4 (br, 1H),3.1 (br, 2H), 2.8 (br, 2H), 1.8 (br, 3H), 1.6 (br, 1H), 1.4 (br, 1H)

Example 791-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole

The procedure given in Example 4 was followed using benzotriazole as areactant, instead of 1H-tetrazole to give1-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-1H-benzotriazole.

1H-NMR (CDCl₃, 500 MHz), δ8.0 (m, 2H), 7.8 (m, 3H), 7.7 (d, 1H), 7.6 (d,1H), 7.5 (m, 3H), 7.4 (m, 1H), 5.8 (d, 1H), 3.4 (br, 1H), 3.0 (br, 2H),2.8 (br, 1H), 2.6 (br, 1H), 1.6 (br, 3H), 1.3 (br, 2H)

Example 802-{(S)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole

The procedure given in Example 2 was followed using benzotriazole as areactant, instead of 1H-tetrazole to give2-{(S)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole.

1H-NMR (CDCl₃, 500 MHz), δ8.0 (s, 1H), 7.8 (m, 7H), 7.5 (m, 2H), 7.4 (m,2H), 5.9 (d, 1H), 3.2 (br, 1H), 3.1 (br, 1H), 2.8 (br, 1H), 2.6 (br,2H), 1.7 (br, 2H), 1.6 (br, 1H), 1.2 (br, 1H)

Example 812-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole

The procedure given in Example 4 was followed using benzotriazole as areactant, instead of 1H-tetrazole to give2-{(R)-naphthalen-2-yl[(3S)-piperidin-3-yl]methyl}-2H-benzotriazole.

1H-NMR (CDCl₃, 500 MHz), δ8.1 (s, 1H), 7.8 (m, 7H), 7.5 (m, 2H), 7.4 (m,2H), 5.9 (d, 1H), 3.2 (br, 1H), 3.0 (br, 2H), 2.7 (br, 1H), 2.5 (br,1H), 1.8 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.3 (br, 1H)

Example 82(3S)-3-[(R)-1-benzothiophene-3-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using3-bromo-1-benzothiophene as a reactant, instead of 2-bromonaphthalene togive(3S)-3-[(R)-1-benzothiophene-3-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.9 (br, 2H), 7.4 (br, 2H), 7.3(br, 1H), 6.4 (br, 1H), 3.7 (br, 1H), 3.5 (br, 2H), 3.2 (br, 2H), 2.0(br, 3H), 1.6 (br, 1H), 1.2 (br, 1H)

Example 83(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using2-bromo-6-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.4 (d,1H), 7.3 (m, 1H), 6.0 (d, 1H), 3.0 (br, 2H), 2.7 (br, 2H), 2.5 (m, 1H),1.8 (br, 2H), 1.6 (br, 1H), 1.4 (br, 1H), 1.2 (br, 1H)

Example 84(3R)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using2-bromo-6-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(S)-(6-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.4 (d,1H), 7.3 (m, 1H), 6.0 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.6 (br, 1H),2.4 (br, 1H), 1.8 (br, 2H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (br, 1H)

Example 85(3S)-3-[(S)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using2-bromo-6-methylnaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (t, 2H), 7.7 (d,1H), 7.6 (s, 1H), 7.4 (d, 1H), 6.0 (d, 1H), 3.0 (br, 2H), 2.7 (br, 2H),2.5 (s, 3H), 2.4 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.4 (br, 1H), 1.2(br, 1H)

Example 86(3S)-3-[(R)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-6-methylnaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(6-methylnaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.0 (s, 1H), 7.8 (t, 2H), 7.7 (d,1H), 7.6 (s, 1H), 7.4 (d, 1H), 5.9 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H),2.6 (br, 1H), 2.5 (s, 3H), 2.4 (br, 1H), 1.7 (br, 1H), 1.5 (br, 1H), 1.4(br, 1H), 1.2 (br, 1H)

Example 87(3S)-3-[(S)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-4-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.2 (d, 1H), 8.0 (m,1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.2 (t, 1H), 6.7 (d, 1H), 3.1 (br, 2H),2.9 (br, 1H), 2.7 (br, 2H), 2.5 (br, 1H), 1.6 (br, 2H), 1.5 (br, 1H),1.2 (br, 1H)

Example 88(3S)-3-[(R)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-4-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(4-fluoronaphthalen-1-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.4 (d, 1H), 8.2 (d, 1H), 7.9 (m,1H), 7.7 (t, 1H), 7.6 (t, 1H), 7.2 (t, 1H), 6.7 (d, 1H), 3.0 (br, 2H),2.9 (br, 1H), 2.7 (br, 1H), 2.4 (br, 1H), 1.8 (br, 2H), 1.5 (br, 1H),1.4 (br, 1H), 1.3 (br, 1H)

Example 89(3S)-3-[(R)-naphthalen-2-yl(4H-1,2,4-triazol-4-yl)methyl]piperidine

The procedure given in Example 4 was followed using 1,2,4-triazole as areactant, instead of 1H-tetrazole to give(3S)-3-[(R)-naphthalen-2-yl(4H-1,2,4-triazol-4-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (s, 1H), 8.0 (s, 1H), 7.9 (s, 1H), 7.8 (m,4H), 7.7 (d, 1H), 7.5 (m, 2H), 5.3 (d, 1H), 3.0 (br, 3H), 2.7 (br, 1H),2.5 (br, 1H), 1.8 (br, 1H), 1.6 (br, 2H), 1.3 (br, 2H)

Example 90(3S)-3-[(S)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperidine

The procedure given in Example 2 was followed using 1,2,4-triazole as areactant, instead of 1H-tetrazole to give(3S)-3-[(S)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.3 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.7 (d,1H), 7.5 (m, 2H), 5.4 (d, 1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.4 (br, 2H),1.6 (br, 4H), 1.2 (br, 1H)

Example 91(3S)-3-[(R)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperdine

The procedure given in Example 4 was followed using 1,2,4-triazole as areactant, instead of 1H-tetrazole to give(3S)-3-[(R)-naphthalen-2-yl(1H-1,2,4-triazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.3 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.7 (d,1H), 7.5 (m, 2H), 5.4 (d, 1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.7 (br, 1H),2.5 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.2 (br, 1H)

Example 92 (3S)-3-[(R)-naphthalen-2-yl(1H-pyrazol-1-yl)methyl]piperidine

The procedure given in Example 4 was followed using pyrazole as areactant, instead of 1H-tetrazole to give(3S)-3-[(R)-naphthalen-2-yl(1H-pyrazol-1-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.0 (s, 1H), 7.8 (m, 3H), 7.5 (m, 5H), 6.2 (s,1H), 5.2 (d, 1H), 3.2 (br, 1H), 3.1 (br, 2H), 2.7 (br, 1H), 2.5 (br,1H), 1.8 (br, 2H), 1.6 (br, 1H), 1.3 (br, 2H)

Example 93(3S)-3-[(S)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using2-bromo-1-benzothiophene as a reactant, instead of 2-bromonaphthalene togive(3S)-3-[(S)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.6 (s, 1H), 7.8 (m, 2H), 7.5 (s, 1H), 7.4(br, 2H), 6.3 (d, 1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.6 (br, 1H), 2.4(br, 1H), 1.8 (br, 3H), 1.5 (br, 1H), 1.3 (br, 1H)

Example 94(3S)-3-[(R)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-1-benzothiophene as a reactant, instead of 2-bromonaphthalene togive(3S)-3-[(R)-1-benzothiophene-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.6 (s, 1H), 7.8 (m, 2H), 7.5 (s, 1H), 7.4(br, 2H), 6.3 (d, 1H), 3.0 (br, 2H), 2.8 (br, 1H), 2.7 (br, 1H), 2.6(br, 1H), 1.8 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H), 1.1 (br, 1H)

Example 95(3S)-3-[(S)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using4-bromo-1,2-difluorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(3)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m,1H), 5.8 (d, 1H), 2.8 (br, 5H), 1.8 (br, 1H), 1.6 (br, 1H), 1.5 (br,1H), 1.2 (br, 1H)

Example 96(3S)-3-[(R)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using4-bromo-1,2-difluorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(3,4-difluorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.2 (m,1H), 5.8 (d, 1H), 2.8 (br, 5H), 1.8 (br, 2H), 1.4 (br, 2H), 1.1 (br, 1H)

Example 97(3S)-3-[(S)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using1-bromo-2,3-dichlorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (t,1H), 6.6 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 2H), 2.4 (br,2H), 1.8 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H), 1.3 (br, 1H)

Example 98(3S)-3-[(R)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using1-bromo-2,3-dichlorobenzene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(2,3-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 7.8 (d, 1H), 7.5 (d, 1H), 7.3 (t,1H), 6.5 (d, 1H), 2.8 (br, 5H), 1.8 (br, 1H), 1.5 (br, 1H), 1.4 (br,1H), 1.3 (br, 1H)

Example 99(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 1 was followed using2-bromo-1-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.2 (m, 1H), 7.8 (m, 2H), 7.7 (d,1H), 7.6 (m, 2H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 1H), 2.6 (br, 2H),2.5 (br, 1H), 2.3 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H),1.3 (br, 1H)

Example 100(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 2 was followed using2-bromo-1-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.2 (m, 1H), 7.8 (m, 2H), 7.7 (d,1H), 7.6 (m, 2H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 1H), 2.6 (br, 2H),2.5 (br, 1H), 2.3 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H),1.3 (br, 1H)

Example 101(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 3 was followed using2-bromo-1-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.7 (d,1H), 7.6 (m, 2H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 2H), 2.6 (br, 1H),2.5 (br, 1H), 1.7 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (br, 1H)

Example 102(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 4 was followed using2-bromo-1-fluoronaphthalene as a reactant, instead of 2-bromonaphthaleneto give(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.5 (s, 1H), 8.1 (m, 1H), 7.8 (m, 2H), 7.7 (d,1H), 7.6 (m, 2H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 2H), 2.6 (br, 1H),2.5 (br, 1H), 1.7 (br, 1H), 1.5 (br, 1H), 1.4 (br, 1H), 1.2 (br, 1H)

Example 103(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 99 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.1 (d, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 6.4 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 2H), 2.5 (s, 3H),2.5 (br, 1H), 2.4 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.4 (br, 1H),1.2 (br, 1H)

Example 104(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 100 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.1 (d, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 6.4 (d, 1H), 3.0 (br, 1H), 2.8 (br, 1H), 2.6 (br, 2H), 2.5 (s, 3H),2.5 (br, 1H), 2.4 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.4 (br, 1H),1.2 (br, 1H)

Example 105(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 101 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.1 (m, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 6.3 (d, 1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.6 (br, 1H), 2.5 (s, 3H),2.4 (br, 1H), 2.2 (br, 1H), 1.7 (br, 1H), 1.5 (br, 2H), 1.2 (br, 1H)

Example 106(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 102 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.1 (m, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 6.3 (d, 1H), 3.0 (br, 1H), 2.8 (br, 2H), 2.6 (br, 1H), 2.5 (s, 3H),2.4 (br, 1H), 2.2 (br, 1H), 1.7 (br, 1H), 1.5 (br, 2H), 1.2 (br, 1H)

Example 107(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 99 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (m, 3H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 7.5 (m, 3H), 6.5 (d, 1H), 3.0 (br, 2H), 2.7 (br, 3H), 2.2 (br, 1H),1.7 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H)

Example 108(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 100 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (m, 3H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (m,2H), 7.5 (m, 3H), 6.5 (d, 1H), 3.0 (br, 2H), 2.7 (br, 3H), 2.2 (br, 1H),1.7 (br, 2H), 1.5 (br, 1H), 1.3 (br, 1H)

Example 109(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 101 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(S)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (m, 3H), 7.9 (t, 1H), 7.8 (d, 1H), 7.7 (d,1H), 7.6 (m, 2H), 7.5 (m, 3H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 2H),2.6 (br, 1H), 2.5 (br, 1H), 2.0 (br, 1H), 1.8 (br, 1H), 1.5 (br, 2H),1.3 (br, 1H)

Example 110(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 102 was followed using5-phenyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3S)-3-[(R)-(1-fluoronaphthalen-2-yl)(5-phenyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.2 (m, 3H), 7.9 (t, 1H), 7.8 (d, 1H), 7.7 (d,1H), 7.6 (m, 2H), 7.5 (m, 3H), 6.5 (d, 1H), 3.0 (br, 1H), 2.9 (br, 2H),2.6 (br, 1H), 2.5 (br, 1H), 2.0 (br, 1H), 1.8 (br, 1H), 1.5 (br, 2H),1.3 (br, 1H)

Example 111(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 83 was followed using5-methyl-1H-tetrazole as a reactant, instead of 1H-tetrazole to give(3R)-3-[(R)-(6-fluoronaphthalen-2-yl)(5-methyl-2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 500 MHz), δ8.0 (s, 1H), 7.8 (m, 3H), 7.4 (d, 1H), 7.3 (m,1H), 5.8 (d, 1H), 3.0 (br, 1H), 2.9 (br, 1H), 2.6 (br, 2H), 2.5 (s, 3H),2.4 (br, 1H), 2.2 (br, 1H), 1.7 (br, 1H), 1.6 (br, 1H), 1.5 (br, 1H),1.2 (br, 1H)

Example 112(3S)-1-butyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 73 was followed using 1-Iodobutane as areactant, instead of iodoethane to give(3S)-1-butyl-3-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.68.5 (s, 1H), 8.0 (d, 1H), 7.7 (m, 4H), 7.4 (d, 2H), 6.1 (d, 1H), 2.2(m, 4H), 2.0 (m, 4H), 1.9 (m, 1H), 1.5 (m, 4H), 1.4 (m, 2H), 1.2 (m, 3H)

Example 113 4-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

A mixture of 2-bromonaphthalene (4.59 mmol) and magnesium (5.508 mmol)was stirred vigorously in anhydrous THF (10 ml) under nitrogenatmosphere for 1 h to prepare naphthalen-2-ylmagnesium bromide solution.To this resulting solution was addedtert-butyl-4-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.836mmol) slowly at 0° C. After 10 min, the reaction mixture was warmed upto room temperature slowly and stirred for 2 hours. This solution wasthen quenched with aqueous NH₄Cl (10 ml) and ethyl acetate (15 ml) wasadded. Organic layer was separated from aqueous layer, washed withbrine. The combined organic layer was dried over anhydrous MgSO₄ andconcentrated in vacuo.

The crude product was dissolved in anhydrous THF. To this solution wasslowly added (R)-2-methyl-CBS-oxazaborolidine (1.0M in toluene, 0.5equiv) at −78° C. After 5 min, borane-THE complex (3 equiv) was addedslowly. The reaction mixture was then transferred into the freezer andleft overnight. The mixture was cooled to 0° C. and water was addeddropwise to quench the reaction. The reaction mixture was diluted withethyl acetate, washed with 5% aq NaOH, water, brine, and dried overMgSO₄. After concentration, the crude product was purified by flashcolumn chromatography with a 4-35% ethyl acetate in hexanes gradient toafford enantiomeric mixture of tert-butyl4-((R)-hydroxy(naphthyl)methyl)piperidine-1-carboxylate.

To a stirred solution of triphenylphosphine (2.754 mmol) and1H-tetrazole (2.754 mmol) in THF (6 ml) was added previously preparedproduct (1.836 mmol) in THF (2 ml) at room temperature. The reactionmixture was stirred for 15 minutes, followed by the dropwise addition ofdiisopropyl azodicarboxylate (3.672 mmol) at 0° C. The solution wasfurther stirred for 1 hour at room temperature. When the reaction wascomplete, the crude mixture was purified with silica gel chromatography(ethyl acetate:hexane=1 : 6).

The resulting product was dissolved in 6% HCl-MeOH solution and allowedto stir for 6 h. The solvent was removed under reduced pressure andbasified with 1N NaOH to afford enantiomeric mixture of4-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine. Enantiomericpure compound of4-[(S)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine was obtainedfrom the enantiomeric mixture using a CHIRALPACK OD-H column(manufactured by Daicel Chemical Industries, Ltd.) as the Prep-LCcolumn, at a column temperature of 25° C., withn-hexane/isopropylalcohol including 0.1% triethylamine(90:10) as theeluent.

1H-NMR (CDCl₃, 200 MHz), δ 8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.7(m, 1H) 7.5 (m, 2H), 5.8 (d, 1H), 3.0 (br, 2H), 2.7 (m, 3H), 1.3 (m, 4H)

Example 114 4-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 113 was followed using(S)-2-methyl-CBS-oxazaborolidine as a reactant, instead of(R)-2-methyl-CBS-oxazaborolidine to give4-[(R)-naphthalen-2-yl(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.5 (s, 1H), 8.0 (s, 1H), 7.8 (m, 3H), 7.7(m, 1H) 7.5 (m, 2H), 5.8 (d, 1H), 3.0 (br, 2H), 2.7 (m, 3H), 1.3 (m, 4H)

Example 115 4-[(S)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine

The procedure was given in Example 113 to give4-[(S)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.4 (s, 1H), 7.4 (d, 2H), 7.1 (d, 2H), 5.5(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.4 (br, 1H), 1.1 (m,3H)

Example 116 4-[(R)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine

The procedure was given in Example 114 to give4-[(R)-naphthalen-2-yl(1H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.4 (s, 1H), 7.4 (d, 2H), 7.1 (d, 2H), 5.5(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.4 (br, 1H), 1.1 (m,3H)

Example 117 4-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 113 was followed using2-bromo-4-methylbenzene as a reactant, instead of 2-bromonaphthalene togive 4-[(S)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.4 (s, 1H), 7.4 (d, 2H), 7.1 (d, 2H), 5.5(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.4 (br, 1H), 1.1 (m,3H)

Example 118 4-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 117 was followed using(S)-2-methyl-CBS-oxazaborolidine as a reactant, instead of(R)-2-methyl-CBS-oxazaborolidine to give4-[(R)-(4-methylphenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.4 (s, 1H), 7.4 (d, 2H), 7.1 (d, 2H), 5.5(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.4 (br, 1H), 1.1 (m,3H)

Example 119 4-[(S)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine

The procedure was given in Example 117 to give4-[(S)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.7 (s, 1H), 7.3 (d, 2H), 7.1 (d, 2H), 5.2(d, 1H), 3.0 (br, 2H), 2.5 (m, 3H), 2.3 (s, 3H), 1.4 (br, 1H), 1.2 (m,3H)

Example 120 4-[(R)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine

The procedure was given in Example 118 to give4-[(R)-(4-methylphenyl)(1H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.7 (s, 1H), 7.3 (d, 2H), 7.1 (d, 2H), 5.2(d, 1H), 3.0 (br, 2H), 2.5 (m, 3H), 2.3 (s, 3H), 1.4 (br, 1H), 1.2 (m,3H)

Example 1214-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure given in Example 113 was followed using1H-[1,2,3]-triazole as a reactant, instead of 1H-tetrazole to give4-[(S)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 7.9 (s, 1H), 7.8 (m, 3H), 7.7 (m, 1H), 7.6(m, 2H), 7.5 (m, 2H), 5.5 (d, 1H), 3.1 (br, 2H), 2.7 (m, 3H), 1.3 (m,4H)

Example 1224-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure given in Example 121 was followed using(S)-2-methyl-CBS-oxazaborolidine as a reactant, instead of(R)-2-methyl-CBS-oxazaborolidine to give4-[(R)-naphthalen-2-yl(2H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 7.9 (s, 1H), 7.8 (m, 3H), 7.7 (m, 1H), 7.6(m, 2H), 7.5 (m, 2H), 5.5 (d, 1H), 3.1 (br, 2H), 2.7 (m, 3H), 1.3 (m,4H)

Example 1234-[(S)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure was given in Example 121 to give4-[(S)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 7.8 (m, 4H), 7.6 (m, 3H), 7.5 (m, 2H), 5.3(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 1.3 (m, 4H)

Example 1244-[(R)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine

The procedure was given in Example 122 to give4-[(R)-naphthalen-2-yl(1H-1,2,3-triazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 7.8 (m, 4H), 7.6 (m, 3H), 7.5 (m, 2H), 5.3(d, 1H), 3.0 (br, 2H), 2.6 (m, 3H), 1.3 (m, 4H)

Example 1254-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 113 was followed using2-bromo-3,4-dichlorobenzene as a reactant, instead of 2-bromonaphthaleneto give 4-[(S)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.5 (s, 1H), 7.6 (s, 1H) 7.4 (d, 2H), 5.5 (d,1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.4 (br, 1H), 1.4 (br, 1H), 1.2 (m, 3H)

Example 1264-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine

The procedure given in Example 125 was followed using(S)-2-methyl-CBS-oxazaborolidine as a reactant, instead of(R)-2-methyl-CBS-oxazaborolidine to give4-[(R)-(3,4-dichlorophenyl)(2H-tetrazol-2-yl)methyl]piperidine.

1H-NMR (CDCl₃, 200 MHz), δ 8.5 (s, 1H), 7.6 (s, 1H) 7.4 (d, 2H), 5.5 (d,1H), 3.0 (br, 2H), 2.6 (m, 3H), 2.4 (br, 1H), 1.4 (br, 1H), 1.2 (m, 3H)

The therapeutic use of the racemic or enantiomerically enrichedcompounds of general structural formula (I), (III) and (IV) and theirpharmaceutically useful salts have been established by the followingtests.

Serotonin Transporter Reuptake Inhibition Assay

The method to test the ability of compounds to inhibit transporters fromreuptake of serotonin followed Gu H. et al., J Biol. Chem., 1994, 269, p7214˜7130.

The recombinant HEK-293 cells with human serotonin transporter wereplated. Test compounds were pre-incubated with cells (2×10⁵/ml) inmodified Tris-HEPES buffer pH 7.1 for 20 minutes at 25° C. and then theywere incubated for additional 10 minutes after 65 nM of [³H]Serotoninwas added. Bound cells were filtered and counted to determine[³H]Serotonin uptake. Reduction of [³H]Serotonin uptake by 50 percent ormore (≧50%) relative to 10 μM fluoxetine indicates significantinhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and0.001 μM for IC50s.

Norepinephrine Transporter Reuptake Inhibition Assay

Norepinephrine transporter reuptake inhibition assay used the methoddescribed by Galli A. et al., J Exp Biol., 1995, 198, p 2197˜2212.

MDCK cells with stably expressed human recombinant norepinephrinetransporter were plated one day. Test compounds were pre-incubated withcells (2×10⁵/ml) in modified Tris-HEPES buffer pH 7.1 for 20 minutes at25° C. and then they were incubated for additional 10 minutes after 25nM of [³H]Norepinephrine was added. A lysate was obtained fromsolubilized cells and the filtered lysate was counted to determine[³H]Norepinephrine uptake. Reduction of [³H]Norepinephrine uptake by 50percent or more (≧50%) relative to 10 μM desipramine indicatessignificant inhibitory activity. Compounds were screened at 10, 1, 0.1,0.01 and 0.001 μM to determine their IC50s.

Dopamine Transporter Reuptake Inhibition Assay

The assay followed the method modified from Pristupa Z. B. et al., Mol.Pharmacol., 1994, p 125˜135.

CHO-K1 cells with human recombinant dopamine transporter were plated.Test compounds were pre-incubated with cells (4×10⁵/ml) in modifiedTris-HEPES buffer pH 7.1 for 20 minutes at 25° C. and then they wereincubated for additional 10 minutes after 50 nM of [³H]Dopamine wasadded. A lysate is obtained from solubilized cells and counted todetermine [³H]Dopamine uptake. Reduction of [³H]Dopamine uptake by 50percent or more (≧50%) relative to 10 μM nomifensine indicatessignificant inhibitory activity. Compounds were tested at 10, 1, 0.1,0.01 and 0.001 μM for IC50s.

The results obtained by testing compounds of the invention are given inthe following table 1.

TABLE 1 Inhibition % at 100 nM Test 5-HT Compound reuptake NE reuptakeDA reuptake Example 1 81% 94% 88% Example 2 98% 85% 85% Example 10 93%87% 93% Example 12 83% 90% 92% Example 13 84% 87% 63% Example 14 76% 70%52% Example 15 75% 98% 99% Example 35 76% 72% 78% Example 67 97% 90% 81%Example 68 96% 57% 63% Example 70 95% 14% 3% Example 71 92% 46% 54%Example 72 86% 6% 2% Example 75 86% −1% 41% Example 80 59% 55% 84%Example 83 96% 78% 66% Example 84 44% 5% −4% Example 85 94% 74% 81%Example 86 93% −1% 35% Example 90 87% 39% 44%

The data in Table 1 show that racemic or enantiomerically enriched novel3 or 4-substituted piperidine derivatives, the compounds of theinvention have a significantly high inhibition potency of the serotonin,norepinephrine, dopamine transporter reuptake. This inhibition ofserotonin, norepinephrine, dopamine transporter reuptake has beenassociated with the treatment of one or more of the CNS disorders suchas depression, anxiety and pain disorder.

Forced Swimming Test in Mice(FST)

The Forced swimming test is an animal model based on the rodent'sbehavioral repertoire for screening drugs with potential antidepressantactivity. As in several other models used for this goal, anuncontrollable stress stimulus produces behavioral changes that aresensitive to antidepressant treatment.

The mice were intraperitoneally treated with the test compound with aninjection volume of 10 mg/kg. The group treated with 30% PEG400 servedas a control group. Thirty minutes following administration, mice wereindividually forced to swim in a transparent glass vessel (14 cm high,11.5 cm in diameter) filled with 10 cm of water at 25° C. The totalduration of immobility (second) was measured during the last 4 minutesof a single 6-min test session. Mice were considered immobile when theymade no further attempts to escape other than the movements necessary tokeep their heads above the water. The potent ability of the compoundswas determined as percent value of reduction in the duration ofimmobility comparing to the control group.

The results obtained by testing compounds of the invention are given inthe following table 2:

TABLE 2 Test Reduction % Compound at 30ip Example 1 56.3% Example 237.5% Example 12 9.7% Example 13 9.4% Example 14 6.4% Example 15 96.5%Example 35 32.7% Example 67 2.4% Example 68 7.1% Example 71 54.0%Example 72 46.7% Example 83 51.8% Example 85 11.3% Example 86 13.4%

Specially the results of forced swimming test(FST) in mice as noted inTable 2 show the compounds of the invention are related to the treatmentof depression.

Marble Burying Test

The Marble burying test is a screening tool for putative anxiolytics. Inthis test, control mice naturally bury glass marbles in the cage beddingand the administration of anxiolytic compounds, including Diazepam,reduces the number of buried marbles. Positive compounds in the marbleburying test including selective serotonin reuptake inhibitor may beespecially beneficial to obsessive-compulsive disorder.

A group of mice was intraperitoneally treated with test compounddissolved in 30% PEG400 with an injection volume of 10 ml/kg. The grouptreated with only 30% PEG400 served as a control group. Thirty minutesafter the treatment, the animals were individually placed in apolycarbonate cage which was same as used for animal housing with anopen top located within a quiet room. Each cage consisted of ⅛ inch cornbedding 5 cm deep. Twenty four clean glass marbles (15 mm diameter) wereevenly spaced in four rows of six on top of the bedding. Each mouse wasleft in the cage for 30 minutes and the number of marbles buried (buriedmore than ½ or ⅔) was counted. The potent ability of the compounds wasdetermined as percent value of reduction in the number of marbles buriedcomparing to the control group.

The results obtained by testing compounds of the invention are given inthe following table 3:

TABLE 3 Test Reduction % at Compound 30ip Example 1 57.5% (at 10ip)Example 2 67.5% (at 20ip) Example 12 91.8% Example 15 75.3% Example 7186.0% Example 83 83.7%

Specially the results of Marble burying test(MB) in mice as noted inTable 3 show the compounds of the invention are related to the treatmentof anxiety.

Acetic Acid Induced Writhing Test (AA Writhing Test)

The Acetic acid-induced writhing test is a well-established nociceptivetest using a chemical stimulus. Although several animal models ofnociceptive tests have been developed to examine and compare theanti-nociceptive effects of different drugs, the anti-nociceptiveeffects of antidepressants appear to be test-dependent. Indeed, theacetic acid-induced writhing test is more sensitive to antidepressantsthan other tests using thermal, mechanical or electrical stimuli.

The animals were subcutaneously treated with the test compound with aninjection volume of 10 ml/kg. The group treated with 30% PEG400 orsaline served as a control group. Thirty minutes later, the mice wereintraperitoneally treated with 0.8% (v/v) acetic acid. Each mouse wasthen placed in a cage for individual observation. The writhing numbersfor 10 minutes were counted. The writhe is operationally defined as acontraction of the abdomen followed by stretching of the hind limbs. Thepotent ability of the compounds was determined as percent value ofreduction in the number of writhing comparing to the control group.

The results obtained by testing compounds of the invention are given inthe following table 4:

TABLE 4 Test Reduction % at Compound 30sc Example 1 70.8% Example 260.6% (at 10sc) Example 12 50.5% Example 13 71.8% Example 15 55.3%Example 68 48.1% (at 10sc) Example 71 48.7% Example 83 84.1% Example 8546.4% (at 10sc)

Specially the results of Acetic acid induced writhing test(AA writhingtest) in mice as noted in Table 4 show the compounds of the inventionare related to the treatment of pain.

In therapeutic use as agents for various CNS disorders such asdepression, anxiety and pain disorder, the compounds of the presentinvention, alone or in combination with pharmaceutically acceptablecarrier, are administered to patients at a dosage of from 0.7 to 7,000mg per day. For a normal human adult with a body weight of approximately70 kg, the administration amount is translated into a daily dose of 0.01to 100 mg per kg of body weight. The specific dosage employed, however,may vary depending upon the requirements of the patient, the severity ofpatient's condition and the activity of the compound. The determinationof optimum dosages for a particular situation must clinically be doneand is within the skill of the art.

In utilizing the compounds of the present invention for the centralnervous system such as depression, anxiety and pain disorder, thecompounds represented by general structural formula (I), (III) and (IV)can be administered in any form or mode which makes the compoundbioavailable in effective amounts, including the oral, rectal,transdermal, subcutaneous, intravenous, intramuscular or intranasalrouts. However it is preferred to administer the compounds orally. Sincethe compounds absorb well orally, it usually will not be necessary toresort to parenteral administration. For oral administration, thecompounds having the general formula (I), (III) and (IV) are preferablycombined with a pharmaceutical carrier. The ratio of the carrier to thecompound of structural formula (I), (III) and (IV) is not critical toexpress the effects of the medicine on the central nervous system, andthey can vary considerably depending on whether the composition is to befilled into capsules or formed into tablets. In tableting, variousedible pharmaceutical carriers or the mixture thereof can be used.Suitable carriers, for example, are a mixture of lactose, diabasiccalcium phosphate and/or corn starch. Other pharmaceutically acceptableingredients can be further added, including lubricants such as magnesiumstearate.

The present invention includes methods of treating depression, anxietyand pain disorder in a mammal which comprises administering thecomposition of the compound of structural formula (I), (III) and (IV) toa mammal in need of therapy.

1-11. (canceled)
 12. A method of treating depression, anxiety and paindisorder in a mammal in need of such treatment in accordance with claim15, which comprises administering to said mammal an effective amount ofa racemic or enantiomerically enriched compound selected from the grouprepresented by the following structural formulae (III):

wherein A, B and R are as defined therein and pharmaceuticallyacceptable salts thereof.
 13. A method of treating depression, anxietyand pain disorder in a mammal in need of such treatment in accordancewith claim 12, which comprises administering to said mammal an effectiveamount of a racemic or enantiomerically enriched compound selected fromthe group represented by the following structural formulae (XXII):

wherein R₁, R₂ and R₃ are identical or different substituents selectedfrom the group consisting of hydrogen, halogen, straight- orbranched-chain alkyl of from 1 to 4 carbon atoms, straight- orbranched-chain alkoxy of from 1 to 3 carbon atoms, nitro, cyano,trifluoromethyl, trifluoromethoxy, methanesulfonyl, phenyloxy, phenyland thienyl; B and R are as defined therein, and pharmaceuticallyacceptable salts thereof.
 14. A method of treating depression, anxietyand pain disorder in a mammal in need of such treatment in accordancewith claim 15, which comprises administering to said mammal an effectiveamount of a racemic or enantiomerically enriched compound represented bythe following structural formulae (IV):

wherein A, B and R are as defined therein, and pharmaceuticallyacceptable salts thereof.
 15. A method of treating depression, anxietyand pain disorder in a mammal in need of such treatment which comprisesadministering to said mammal an effective amount of a racemic orenantiomerically enriched 3- or 4-substituted piperidine compoundrepresented by the following structural formula (I):

and pharmaceutically acceptable salts thereof, wherein: A is selectedfrom the group consisting of phenyl, naphthyl, benzothiophenyl, pyridyl,quinolyl and isoquinolyl, which may be substituted with one or moreidentical or different substituents selected from the group consistingof hydrogen, halogen, straight- or branched-chain alkyl of from 1 to 4carbon atoms, straight- or branched-chain alkoxy of from 1 to 3 carbonatoms, nitro, cyano, trifluoromethyl, trifluoromethoxy, methanesulfonyl,phenyloxy, phenyl and thienyl; B is an azole selected from the groupconsisting of imidazole, pyrazole, triazole, benzotriazole, tetrazole,5-methyl tetrazole and 5-phenyl tetrazole which are linked by nitrogenas represented by the following structural formulae (II); and

one of X and Y is CH₂ and the other is N—R wherein R is hydrogen or aC₁₋₄ alkyl group.